7-(substituted)-9-(substituted-glycyl)amido-6-demethyl-6 - desoximetasone, intermediate compounds, methods for their production, treatment method and composition

 

(57) Abstract:

6-Demethyl-6-desoximetasone formula 1, where R is halogen or NR1R2when R1is hydrogen, R2is methyl, ethyl, n-propyl, and when R1is methyl or ethyl, R2is methyl, ethyl, n-propyl, n-butyl; R3is hydrogen, C4-8- alkyl, R4is hydrogen, methyl, ethyl; W - hydroxylamino, C7-12- alkyl-monosubstituted amino, or R3and W taken together are -(CH2)n(R5)N-, n=3; R5- TRIFLUOROACETYL or their pharmaceutically acceptable salts or metal complexes. Connection 1 find antibiotic activity against a wide spectrum of organisms including organisms which are resistant to tetracyclines and are useful as antibiotic funds. 6 C. and 5 C.p. f-crystals, 4 PL.

The invention relates to previously unknown [4S-(4 alpha, 12-alpha)] -4-(dimethylamino)-7-(substituted) -9-[(substituted-glycyl)amido] -1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12, 12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide, hereinafter called the 7-(substituted)-9-[(substituted-glycyl)amido]-6-demethyl-6 - desoximetasone, that shows antibiotic activity against a wide spectrum of organizations is ntibiotics funds.

The invention also relates to previously unknown 9-[(haloacyl)amido] -7-(substituted)-6-demethyl-6-deoxytetranucleoside intermediates, useful for previously unknown compounds that meet present invention, and previously unknown ways to obtain previously unknown compounds and intermediate compounds.

The present invention relates to previously unknown 7-(substituted)-9-[(substituted-glycyl)amido]-6-demethyl-6 - desoximetasone represented by formulas I and II, which have antibacterial activity, methods of treatment of infectious diseases in warm-blooded animals with the use of these new compounds, pharmaceutical preparations containing these compounds, previously unknown intermediate compounds and methods of obtaining these compounds. More specifically, the present invention relates to compounds of formulas I and II, which increased antibacterial activity against strains resistant to tetracycline, but also reveal a high level of activity against strains which are normally susceptible to tetracyclines.

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In formulas I and II, R is a halogen selected from the group that includes bromine, chlorine, fluorine and iodine, or R is I, n-through, 1-mtilatila, n-bucilina, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethylene group,

and, if R1is a methyl or ethyl group, then

R2is methyl, ethyl, n-through, 1-mtilatila, n-bucilina, 1-methylpropyl or 2-methylpropyl group,

and, if R1- n-through the group, then

R2- n-through, 1-mtilatila, n-bucilina, 1-methylpropyl or 2-methylpropyl group,

and, if R1- mtilatila group, then

R2- n-bucilina, 1-methylpropyl or 2-metaproperty group,

and, if R1- n-bucilina group, then

R2- n-bucilina, 1-methylpropyl or 2-methylpropyl group,

and, if R1- 1-methylpropyl group, then

R2- 2-methylpropyl group;

R3- is selected from the group comprising hydrogen;

(C4-C8) alkyl group with straight and branched chain selected from the group comprising bucilina, isobutylene, pentilla, hexeline, Reptilia and anjilina group;

- mercapto (C1-C4) alkyl group selected from the group comprising mercaptomerin, - mercaptoethylamine, - m is Brenna from the group which includes hydroxymethylene, -hydroxyethylene, - hydroxy-1-mtilatila and - hydroxiproline group;

carboxyl (C1-C8) alkyl group;

(C6-C10) aryl group selected from the group comprising phenyl, - naftalina and - naftalina group;

substituted (C6-C10) aryl group (substitution is made from the group comprising hydroxy-group, halogen, (C1-C4-alkoxygroup, trihalo (C1-C3) alkyl group, nitro-, amino-, cyano, (C1-C4) alkoxycarbonyl group, (C1-C3) alkylamino carboxypropyl);

(C7-C9) kalkilya group selected from the group comprising benzyl, 1-phenylethylene, 2-phenylethylene and phenylpropionate group;

substituted (C7-C9) kalkilya group (substitution is from a group that includes holograph, (C1-C4) alkyl group, a nitrogroup, a hydroxy-group, amino group, mono - or disubstituted by ( C1-C4) alkylamino, (C1-C4) alkoxygroup, (C1-C4) alkylsulfonyl group, cyano and carboxypropyl);

R4is selected from hydrogen and (C1- the traveler, bucilina, isobutylene, pentalina and exilda group;

if the group R3is not the same as the group R4then stereochemical state of the asymmetric carbon (i.e. the carbon bearing the Deputy W) may respond to either the racemate (DL) or the individual enantiomers (L or D);

W is selected from the group comprising gidroksilaminopurina; (C7-C12) alkyl monosubstituted amino group with a straight or branched alkyl group, and substitution is made from a group that includes Reptilia, anjilina, Danilina, decile, angellina, Godzilla group and diastereoisomers and enantiomers mentioned branched alkyl monosubstituted amino group; (C1-C4) peralkaline straight or branched chain, which is selected from the group comprising triptoreline, 2,2,2-triptoreline, 3,3,3-cryptosporella, 3,3,3,2,2-pentafluoropropyl, 2,2-deformability, 4,4,4-triptoreline and 3.3-deformational group; monosubstituted (C3-C8) cycloalkylation, and the Deputy is selected from the group comprising cyclopropyl, TRANS-1,2-dimethylcyclopropane, CIS-1,2-dimethylcyclopropane, cyclobutyl,t-2-ilen group and diastereoisomers and enantiomers mentioned monosubstituted (C3-C8) cycloalkylation;

(C4-C10) cycloalkyl alkyl monosubstituted amino group, and the substitution is made from the group comprising (cyclopropyl)methyl, (cyclopropyl)ethyl, (cyclobutyl)methyl, (TRANS-2-methylcyclopropyl)methyl, and (CIS-2-methylcyclohexyl)methyl group; a (C3-C10)Alchemilla and Alchemilla monosubstituted amino group, and the Deputy is selected from the group comprising allyl, 3-bucinellina (CIS - or TRANS-position is obtained), 2-penttila, proponila, 4-octenidine, 2,3-dimethyl-2-bucinellina, 3-methyl-2-bucinellina, 2-cyclopentenyl and 2-cyclohexenyl group;

(C6-C10) aryl monosubstituted amino group, and the substitution is made from the group comprising phenyl and naftalina group; (C7-C10) aralkylamines, and shall be replaced from the group comprising benzyl, 2-phenylethylene, 1-phenylethylene, 2-(naphthyl)methyl, 1-(naphthyl)methyl and phenylpropionate group; a substituted (C6-C10)aryl monosubstituted amino group (substitution is made from the group comprising (C1-C5)acyl group, (C1-C5) alluminare, (C1< alkoxygroup, (C1-C4) alkoxycarbonyl group, (C1-C4) alkylsulfonyl group, amino group, carboxypropyl, cyano, halogen, hydroxy-group, a nitrogroup and triploid (C1-C3) alkyl group; disubstituted by (C6-C14) alkylamino straight or branched symmetrical circuit, and shall be replaced from the group comprising dibutyl, Diisobutyl, di-sec-bucilina, daintily, Diisobutylene, di-sec-pencilina, vexilla, diisodecyl and di-sec-exilda group;

symmetrical disubstituted (C6-C14) cycloalkylation, and shall be replaced from the group comprising dicyclopropyl, dicycloverine, Dicyclopentadiene, di(dicyclopropyl, dicycloverine, Dicyclopentadiene, di(dicyclopropyl) methyl, dicyclohexylurea and bicycloheptene group; disubstituted by (C3-C14) alkylamino straight or branched unsymmetrical chain, which has more than the number of carbons in the substitution is no more than 14; unsymmetrical disubstituted (C4-C14) cycloalkylation, in which the total number of carbons in the substitution is no more than 14; (C2-C8) azicip, which includes 4-methylpiperidino, 4-hydroxypiperidine, 4-(hydroxymethyl)piperidino, 4-(aminomethyl)piperidino, CIS-3,4-dimethylpyrimidinol, TRANS-3,4-dimethylpyrimidine, 2-azabicyclo[2.1.1] Gex-2-ilen, 5-azabicyclo[2.1.1] Gex-5-ilen, 2-azabicyclo[2.2.1] hept-2-ilen, 7-azabicyclo[2.2.1] hept-7-ilen, 2-azabicyclo[2.2.2] Oct-2-ilen group and diastereoisomers and enantiomers mentioned (C2-C8) azacycloheptane and substituted (C2-C6) azacycloheptane group; substituted 1-isoxazolidine group, and substitution is made from the group comprising 2-(C1-C3) alkylbiphenyls, 3-(C1-C3) alkylsalicylate, tetrahydroquinoline and 3,4-dihydroxyindoline group; [1,n]-dietetically and substituted [1, n]-dietetically group selected from the group comprising piperazinilnom, 2-(C1-C3) alkylpiperazine, 4-(C1-C3) alkylpiperazine, 2,4-dimethylpiperidine, 4-(C1-C4) alkoxyphenyl, 4-(C6-C10) aryloxypropanolamine, 4-hydroxypiperidine, 2,5-diazabicyclo[2.2.1]hept-2-ilen, 2,5-diaza-5-methylbicyclo[2.2.1]-hepta-2-ilen, 2,3-diaza-3-methylbicyclo[2.2.2] -Oct-2-azacycloheptane and substituted [1,n]-dietaryguidelines group; 1-asatullayevna and substituted 1-asatullayevna group selected from the group comprising thiomorpholine, 2-(C1-C3) alkyldiphenylamine and 3-(C3-C6) cycloalkylcarbonyl group; N-Azolla and substituted N-Azolla group selected from the group comprising 1-imidazolidinyl, 2-(C1-C3) alkyl-imidazoline, 3-(C1-C3) alkyl-1-imidazolidinyl, 1-pyrrolidine, 2-(C1-C3) alkyl-1-pyrrolidine, 3-(C1-C3) alkyl-1-pyrrolidine, 1-pyrazolidine, 3-(C2-C3) alkyl-1-pyrazolidine, indayla, 1-(1,2,3-triazoline); 4-(C1-C3) alkyl-1-(1,2,3-triazoline), 5-(C1-C3) alkyl-1-(1,2,3-triazoline), 4-(1,2,4-triazoline, 1-tetrataenia, 2-tetrataenia and benzimidazolyl group; (heterocycle) amino group mentioned heterocyclic group selected from the group comprising 2 - or 3-furazilina, 2 - or 3-thienyl, 2-, 3 - or 4-perederina, 2 - or 5-pyridazinyl, 2-piratininga, 2-(imidazolidine), (benzimidazolyl) and (benzothiazolinone) group and substituted (heterocycle) the amino group (substitution is (C-C) alkyl group with straight or branched chain) (heterocycle)methylaminopropyl-pyridylmethylamine, 2 - or 5-pyridazinedione, 2-personalitymanager.tpo, 2-(imidazolyl)methylaminopropyl, (benzimidazolyl)methylaminopropyl and (benzothiazolyl)methylaminopropyl and substituted (heterocycle) methylaminopropyl (the substitution is made (C1-C6) alkyl group with straight or branched chain); carboxy (C2-C4) alkylamino selected from the group comprising aminouksusnoy acid - aminopropionic acid - aminopropionic acid - butyric acid, - aminobutyric acid and the enantiomers mentioned carboxy (C2-C4) alkylamino; 1,1-substituted Gerasimova selected from the group comprising 1,1-dimethylhydrazine, N-aminopiperidine group, 1,1-diethylhydrazine and N-aminopyrrolidine group; (C1-C4) alkoxyamino, and shall be replaced from the group comprising methoxy group, ethoxypropan, n-propoxylate, 1-methylethoxy, n-butoxypropyl, 2-methylpropoxy, and 1,1-dimethylaminopropan, (C3-C8) ziklooksigenaza selected from the group comprising cyclopropane, TRANS-1,2-dimethylcyclopropane, CIS-1,2-dimethylcyclopropane, cyclobutenyl xygraph, bicyclo[2.2.2] -Oct-2-roxyrama and diastereoisomers and enantiomers mentioned (C3-C8) cycloalkylimines; (C6-C10) allacciamento selected from the group comprising phenoxyimino, 1-naphthylacetamide and 2-naphthalocyanine; (C7-C11- arielalexisxrp, and shall be replaced from the group comprising benzyloxy, 2-venlafaxina, 1-venlafaxina, 2-(naphthyl)methoxy group, 1-(naphthyl)methoxy group and phenylpropoxy; [or (C1-C3) - acylamide] alkylamino, and shall be replaced from the group comprising 2-(formamido) ethyl, 2-(acetamido) ethyl, 2-(propionamido)ethyl, 2-(acetamido) through 2-(formamido) through the group, and the enantiomers mentioned [or (C1-C3) acylamide] alkylamino; or (C1-C3- alkoxyalkanols, and shall be replaced from the group comprising 2-methoxyaniline, 2-accosiation, 2,2-diethoxyaniline, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropionate, 3,3-diethoxypropionate group, and the enantiomers mentioned - or - (C1-C3) alkoxyalkanols; -,- or - (C2-C4) hidroxil the other, 3-hydroxiproline and 4-hydroxybutyrate group;

or R3and W taken together are selected from -(CH2)n(R5)N - with n from three to four and-CH2CH(OH)CH2(R5)N -, where R5is selected from hydrogen and (C1-C3) acyl group and acyl group is selected from the formal, acetyl, propionamido and (C2-C3) galvalloy group, the latter is selected from chloroceryle, bromacetyl, trifluoracetyl, 3,3,3-triphosphopyridine and 2,3,3-triphosphopyridine group;

R6is selected from the group comprising hydrogen; (C1-C3) alkyl group with straight or branched chain selected from the group comprising methyl, ethyl, n-sawn or 1-mtilatila group; (C6-C10) aryl group selected from the group comprising phenyl, - naftalina or naftalina group; (C7-C9) kalkilya group, such as benzyl, 1-phenylethylene, 2-phenylethylene or phenylpropionate group; heterocyclic group with five-membered aromatic or saturated ring containing one heteroatom of nitrogen, oxygen, sulfur or selenium, with optional benzole or pyridoxol, scandens Danilina, 2-pyrrolidinone, tetrahydrofuranyl, benzofuranyl, tetrahydrothiophene, thienyl, benzothiazoline or selenazoline group, or a five-membered aromatic ring containing two such heteroatoms as nitrogen, oxygen, sulfur or selenium, optionally having a benzo or pyridoxol condensed with:

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such as imidazolidine, pyrazolidine, benzimidazolyl, oxazolidine, benzoxazolinone, indazolinone, triazoline, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b] Peregrina or pyridylmethylene, or five-membered saturated ring containing one or two heteroatom such as nitrogen, oxygen, sulfur or selenium, and adjacent appended heteroatom of oxygen, i.e.

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(where

A is selected from the group comprising hydrogen; (C1-C4) alkyl group with straight or branched chain; C6- aryl group; a substituted C6- aryl group (substitution is from a group that includes holograph, (C1-C4- alkoxygroup, trihalo (C1-C3) alkyl group, a nitrogroup, amino, cyano, (C1-C4) alkoxycarbonyl group, (C1-C3) alkylamino or carboxy what I 2-phenylethylene or phenylpropionate group, such as - butyrolactam, - butyrolactone, imidazolidinone or N-aminoimidazole or six-membered aromatic ring containing one to three nitrogen heteroatoms, such as perederina, pyridinoline, piratininga, SIM trainline, ansim-trainline, pyrimidinyl or (C1-C3) - alkylthiomethyl group, or six-membered saturated ring containing one or two heteroatoms, such as nitrogen, oxygen, sulfur or selenium, and adjacent appended heteroatom of oxygen, such as 2,3-dioxo-1-piperazinilnom, 4-ethyl-2,3-dioxo-1-piperazinilnom, 4-methyl-2,3-dioxo-1-piperazinilnom, 4-cyclopropyl-2-dioxo-1-piperazinilnom, 2-dioxaborolane, 2-dioxothiazolidine group; or the group -(CH2)COOR8with a value of n ranging from zero to four, where R8is selected from the group comprising hydrogen: alkyl (C1-C3group with a straight or branched chain selected from the group comprising methyl, ethyl, n-sawn or 1-mtilatila group; or (C6-C10) aryl group selected from the group comprising phenyl, - naftalina or naftalina group;

R7th chain, selected from the group comprising methyl, ethyl, n-sawn or 1-mtilatila group; (C6-C10) aryl group selected from the group comprising phenyl, - naftalina or naftalina group; (C7-C9) kalkilya group, such as benzyl, 1-phenylethylene, 2-phenylethylene or phenylpropionate group; heterocyclic group with five-membered aromatic or saturated ring containing one heteroatom, such as nitrogen, oxygen, sulfur or selenium, optionally having a benzo or pyridoxol condensed with:

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such as pyrrolidine, N-methylindoline, indayla, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolidinone, tetrahydrofuranyl, furazilina, benzofuranyl, tetrahydrothiophene, thienyl, benzothiazoline or selenazoline group, or a five-membered aromatic ring containing two heteroatoms such as nitrogen, oxygen, sulfur or selenium, with optional - benzo - or pyridoxol condensed with:

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such as imidazolidine, pyrazolidine, benzimidazolyl, oxazolidine, benzoxazolinone, thiazolidine, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]Peregrina or pyridylmethylene or selenium, and attached adjacent the oxygen atom, i.e.

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(where

A is selected from the group comprising hydrogen; (C1-C4) alkyl group with straight or branched chain; C6- aryl group; a substituted C6- aryl group (substitution is from a group that includes holograph, (C1-C4- alkoxygroup, trihalo (C1-C3) alkyl group, a nitrogroup, amino, cyano, (C1-C4) alkoxycarbonyl group, (C1-C3) alkylamino or carboxypropyl); (C7-C9) kalkilya group selected from the group comprising benzyl, 1-phenylethylene, 2-phenylethylene or phenylpropionate group, such as - butyrolactam, - butyrolactone, imidazolidinone or N-iminoimidazolidine or six-membered aromatic ring containing one to three nitrogen heteroatoms, such as perederina, pyridinoline, piratininga, SIM trainline, Nasim-trainline, pyrimidinyl or (C1-C3) alkyldiphenylamine group; or six-membered saturated ring containing one or two heteroatoms, such as nitrogen, oxygen, sulfur or selenium, and adjacent appended heteroatom KIS is Naya, 4-cyclopropyl-2-dioxo-1-piperazinilnom, 2-dioxaborolane, 2-dioxothiazolidine group;

or the group -(CH2)nCOOR8with n ranging from zero to four, where R8is selected from the group comprising hydrogen; (C1-C3) alkyl group with straight or branched chain selected from the group comprising methyl, ethyl, n-sawn or 1-mtilatila group; or (C6-C10)aryl group selected from the group comprising phenyl, - naftalina or naftalina group; with the proviso that R6and R7cannot be simultaneously hydrogen, or R6and R7taken together, represent a group -(CH2)2B (CH2)2- where B is selected from the group comprising (CH2)nwith the value of n in the range from zero to one, -NH-N(C1-C3) an alkyl group (straight or branched chain), N (C1-C4) alkoxygroup, oxygen, sulfur or substituted related nuclear education, selected from the group which includes (L or D) Proline, ethyl (L or D) prolinate have been obtained, morpholine, pyrrolidine or piperidine; and the pharmacologically acceptable organic or inorganic salts or metal complexes, the which

R is a halogen selected from the group that includes bromine, chlorine, fluorine and iodine; or R is a group-NR1R2and, when R represents a group-NR1R2,

R1is hydrogen;

R2is methyl, ethyl, n-through, 1-mtilatila, n-bucilina, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethylene group; and when R1is a methyl or ethyl group,

R2is methyl, ethyl, n-through, 1-mtilatila, n-bucilina, 1-methylpropyl or 2-methylpropyl group;

R3is selected from the group comprising hydrogen; (C4-C8) alkyl group with straight or branched chain selected from the group comprising bucilina, isobutylene, pentilla, hexeline, Reptilia and anjilina group; hydroxy (C1-C4) alkyl group selected from the group comprising hydroxymethylene, - hydroxyethylene, -hydroxy-1-mtilatila and - hydroxiproline group; carboxyl- (C1-C8) alkyl group; a (C6-C10) aryl group selected from the group comprising phenyl, - naftalina and - naftalina group; a substituted (C6-C10) aryl group (substitution production is alkoxycarbonyl group and carboxypropyl); (C7-C9) kalkilya group selected from the group comprising benzyl, 1-phenylethylene, 2-phenylethylene and phenylpropionate group; a substituted (C7-C9) - kalkilya group (substitution is from a group that includes holograph, (C1-C4) alkyl group, (C1-C4) alkoxygroup, (C1-C4) alkylsulfonyl group, cyano and carboxypropyl);

R4is selected from the group comprising hydrogen and (C1-C4) alkyl group selected from the group comprising methyl, ethyl, sawn, ISO-propyl, bucilina and isobutylene group;

when the group R3not corresponds to R4, stereochemical state of the asymmetric carbon (i.e. the carbon bearing the Deputy W) may respond to either the racemate (DL) or the individual enantiomers (L or D);

W is selected from the group comprising gidroksilaminopurina; (C7-C12) alkyl (straight or branched chain) monosubstituted amino group, and the substitution is made from a group that includes Reptilia, anjilina, Danilina, decile, angellina, Godzilla group and diastereoisomers and enantiomers mentioned rasvet group, moreover, the substitution is from a group that includes cyclopropyl, TRANS-1,2-dimethylcyclopropane, CIS-1,2-dimethylcyclopropane, cyclobutyl, cyclopentamine, tsiklogeksilnogo, cycloheptyl, cyclooctyl group and diastereoisomers and enantiomers mentioned (C3-C8) cycloalkyl monosubstituted amino group; (C1-C4) peralkaline straight or branched chain selected from the group comprising 2,2,2-triptoreline, 3,3-cryptosporella, 2,2-deformability and 3.3-deformational group; [(C4-C10)cycloalkyl] alkyl monosubstituted amino group, and the substitution is made from the group comprising (cyclopropyl) methyl, (cyclopropyl)ethyl, (cyclobutyl)methyl, (TRANS-2-methylcyclopropyl)methyl, and (CIS-2-methylcyclohexyl)methyl group; a (C3-C10) Alchemilla and Alchemilla monosubstituted amino group, and the substitution is made from a group comprising allyl, 3-bucilina, 2-bucinellina (C CIS - or TRANS-position), 2-penttila, proponila, 4-octenidine, 2,3-dimethyl-2-bucinellina and 3-methyl-2-bucinellina group; (C6-C10) aryl monosubstituted amino group, and the substitution of production the substitution is made from the group which includes benzyl, 2-phenylethylene, 1-phenylethylene, 2-(naphthyl) methyl, 1-(naphthyl) methyl and phenylpropionate group; disubstituted by (C6-C14) alkylamino straight or branched symmetrical circuit, and shall be replaced from the group comprising dibutyl, Diisobutyl, di-sec-bucilina, daintily, Diisobutylene and di-sec-pencilina group; symmetrical disubstituted (C6-C14) cycloalkylation, and shall be replaced from the group comprising dicyclopropyl, dicycloverine, Dicyclopentadiene and di(dicyclopropyl)methyl group; disubstituted by (C3-C14) alkylamino straight or branched unsymmetrical circuit, which upon substitution, the total number of carbon atoms is not more than 14; unsymmetrical disubstituted (C4-C14-cycloalkylation, which upon substitution, the total number of carbon atoms does not exceed 14; (C2-C8) azacycloheptane group and substituted (C2-C8) azacycloheptane group, and substitution is made from the group comprising 4-methylpiperidine, 4-hydroxypiperidine, 4-(hydroxymethyl) piperidine, 4-(aminomethyl) piperidine, CIS-3,4-dimethylpyrrole diastereoisomers and enantiomers mentioned (C2-C8) azacycloheptane group; substituted 1-ajoxicillin group, and substitution is made from the group comprising 2-((C1-C3) alkylbiphenyls, 3-(C1-C3) alkylsalicylate and tetrahydroquinoline group; [1,n]-dietetically group and substituted [1,n]-dietetically group selected from the group comprising piperazinilnom, 2-(C1-C3) alkylpiperazine, 4-(C1-C3) alkylpiperazine, 2,4-dimethylpiperidine, 4-(C1-C4) alkoxyphenyl, 4-(C6-C10) aryloxypropanolamine, 4-hydroxypiperidine, 2,3-diaza-3-methylbicyclo[2.2.2] Oct-2-ilen, 2,5-diaza-5,7-dimethylbicyclo[2.2.2]-oxt-2-ilen group and diastereoisomers and enantiomers referred to [1,n]-dietaryguidelines group and substituted [1,n]-dietaryguidelines group; 1-asatullayevna group and substituted 1-asatullayevna group selected from the group comprising thiomorpholine, 2-(C1-C3) alkyldiphenylamine and 3-(C3-C6) cycloalkylcarbonyl group; N-Azolla group and substituted N-Azolla group selected from the group comprising 1-imidazolidinyl, 1-pyrrolidine, 1-, -tetrataenia, 2-tetrataenia and benzimidazolyl group; (heterocycle) methylaminopropyl selected from the group comprising 2 - or 3-feniletilamina, 2 - or 3-titillating, 2-, 3 - or 4-pyridylmethylamine, 2 - or 5-pyridinemethanol, 2-piperazinylmethyl, 2-(imidazolyl)methylaminopropyl, (benzimidazolyl) methylaminopropyl and (benzothiazolyl) methylaminopropyl and substituted (heterocycle)methylaminopropyl (the substitution is made (C1-C6) alkyl group with straight or branched chain); carboxy (C2-C4) alkylamino selected from the group comprising aminouksusnoy acid - aminopropionic acid - aminopropionic acid - butyric acid and a - aminobutyric acid and the enantiomers mentioned carboxy (C2-C4) alkylamino; 1,1-substituted Gerasimova selected from the group comprising 1,1-dimethylhydrazine, N-aminopiperidine group and 1,1-diethylhydrazine; (C1-C4) alkoxyamino, and substitution are made from the group comprising methoxy group, AtaSigorta, n-propoxylate, 1-methylethoxy, n-butoxypropyl, 2-methylpropoxy and 1,1-dimethylether the Rance-1,2-dimethylcyclopropane, CIS-1,2-dimethylcyclopropane, cyclobutene and diastereoisomers and enantiomers mentioned (C3-C8) cycloalkylimines; (C6-C10-allacciamento selected from the group comprising phenoxyimino, 1-naphthylacetamide and 2-naphthalocyanine; (C7-C11)arielalexisxrp, and shall be replaced from the group comprising benzyloxy, 2-venlafaxina, 1-venlafaxina, 2-(naphthyl) methoxy group, 1-(naphthyl) methoxy group and phenylpropoxy; [or (C1-C3) acylamide]alkylamino, and shall be replaced from the group comprising 2-(formamido) ethyl, 2-(acetamido) ethyl, 2-(propionamido) ethyl, 2-(acetamido) through 2-(formamido) through the group, and the enantiomers mentioned [or (C1-C3) acylamide]alkylamino; or (C1-C3) alkoxyalkanols, and shall be replaced from the group comprising 2-methoxyaniline, 2-ethoxyethylene, 2,2-diethoxyaniline, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropionate, 3,3-diethoxypropionate group, and the enantiomers mentioned - or - (C1-C3) alkoxyalkanols; -, - or - (C2supplemented flax, 3-hydroxiproline and 4-hydroxybutyrate group;

or R3and W taken together are selected from the group comprising the group (CH2)n(R5)N - with n being equal to three or four, and the group-CH2CH(OH)CH2)(R5)N-, where R5is selected from hydrogen and (C1-C3) acyl group and acyl group is selected from the group which includes formyl, acetyl, propylaniline and (C2-C3) Galiullina group selected from chloroceryle, bromacetyl, trifluoracetyl, 3,3,3-triphosphopyridine, 2,3,3-triphosphopyridine group;

R2is selected from the group comprising hydrogen and (C1-C3) alkyl group with straight or branched chain selected from the group comprising methyl, ethyl, n-sawn or 1-mtilatila group; (C6-C10) aryl group selected from the group comprising phenyl, -naftalina or naftalina group; (C7-C9) kalkilya group, such as benzyl, 1-phenylethylene, 2-phenylethylene or phenylpropionate group; heterocyclic group with five-membered aromatic or saturated ring containing one heteroatom, such as nitrogen, oxygen, sulfur or what I N-methylindoline, indayla, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolidinone, tetrahydrofuranyl, furazilina, benzofuranyl, tetrahydrothiophene, thienyl, benzothiazoline or selenazoline group; or a five-membered aromatic ring containing two heteroatoms such as nitrogen, oxygen, sulfur or selenium, optionally having a benzo or pyridoxol condensed with:

< / BR>
such as imidazolidine, pyrazolidine, benzimidazolyl, oxazolidine, benzoxazolinone, indazolinone, thiazolidine, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b] Peregrina or pyridylmethylene group; or a five-membered saturated ring containing one or two heteroatoms, such as nitrogen, oxygen, sulfur or selenium, and adjacent appended heteroatom of oxygen, i.e.

< / BR>
(where A is selected from the group comprising hydrogen; (C1-C4) alkyl group with straight or branched chain; C6-aryl group; a (C7-C9) kalkilya group selected from the group comprising benzyl, 1-phenylethylene, 2-phenylethylene or phenylpropionate group),

such as butyrolactone, - butyrolactone, imidazolidinone or N-aminoil R8is selected from the group comprising hydrogen; (C1-C3) alkyl group with straight or branched chain selected from the group comprising methyl, ethyl, n-sawn or 1-mtilatila group; or (C6-C10) aryl group selected from the group comprising phenyl, - naftalina or naftalina group;

R7is selected from the group comprising hydrogen; (C1-C3) alkyl group with straight or branched chain selected from the group comprising methyl, ethyl, n-sawn or 1-mtilatila group; (C6-C10)aryl group selected from the group comprising phenyl, - naftalina or naftalina group; (C7-C9) kalkilya group, such as benzyl, 1-phenylethylene, 2-phenylethylene or phenylpropionate; heterocyclic group with five-membered aromatic or saturated ring containing one heteroatom, such as nitrogen, oxygen, sulfur or selenium, optionally having a benzo or pyridoxol condensed with:

< / BR>
such as pyrrolidine, N-methylindoline, indayla, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-perrigrine, tetrahydrofuranyl, furazilina, benzofuran is Kim ring, containing two heteroatoms such as nitrogen, oxygen, sulfur or selenium, optionally having a benzo or pyridoxol condensed with:

< / BR>
such as imidazolidine, pyrazolidine, benzimidazolyl, oxazolidine, benzoxazolinone, indazolinone, thiazolidine, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b] Peregrina or pyridylmethylene group; or a five-membered saturated ring containing one or two heteroatoms, such as nitrogen, oxygen, sulfur or selenium, and adjacent appended heteroatom of oxygen, i.e.

< / BR>
(where A is selected from the group comprising hydrogen; (C1-C4) alkyl group with straight or branched chain; C6-aryl group; a (C7-C9) kalkilya group selected from the group comprising benzyl, 1-phenylethylene, 2-phenylethylene or phenylpropionate group)

such as butyrolactone, - butyrolactone, imidazolidinone or N-iminoimidazolidine group; or the group -(CH2)nCOOR8with a value of n ranging from zero to four, where R8is selected from the group comprising hydrogen; (C1-C3) alkyl group with straight or branched chain, selected from the group which vrenna from the group which includes phenyl, - naftalina or naftalina; with the proviso that R6and R7cannot be simultaneously hydrogen;

or R6and R7taken together, represent a group -(CH2)2B(CH2)2-, in which B is selected from the group comprising (CH2)nwith the value of n in the range from zero to one, -NH-N (C1-C3) an alkyl group (straight or branched chain), -N (C1-C4) alkoxygroup, oxygen, sulfur or substituted related education, selected from the group which includes (L or D) Proline, ethyl (L or D)prolinate have been obtained, morpholine, pyrrolidine or piperidine; and the pharmacologically acceptable organic and inorganic salts or metal complexes.

Especially preferred compounds are compounds of formulas I and II, in which

R is a halogen selected from the group that includes bromine, chlorine, fluorine and iodine; or R is a group-NR1R2and, when R represents a group-NR1R2and R1represents hydrogen,

R2is methyl, ethyl, n-through, 1-mtilatila, n-bucilina, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethylene group; and when R1 the other, 1-methylpropyl or 2-methylpropyl group;

R3is selected from the group comprising hydrogen; (C4-C6) alkyl group with straight or branched chain selected from the group comprising bucilina, isobutylene, pentilla and exilda group; (C6-C10) aryl group selected from the group comprising phenyl, - naftalina and - naftalina group; (C7-C9) kalkilya group selected from the group comprising benzyl, 1-phenylethylene, 2-phenylethylene and phenylpropionate group;

R4is selected from the group comprising hydrogen and (C1-C3) alkyl group selected from the group comprising methyl, ethyl, sawn, and ISO-propyl group; when R3does not meet R4, stereochemical state of the asymmetric carbon (i.e. the carbon bearing the Deputy W) can respond to the racemate (DL) or the individual enantiomers (L or D);

W is selected from the group comprising (C7-C12) alkyl monosubstituted amino group with a straight or branched chain, and the replacement is from a group that includes Reptilia, anjilina, Danilina, decile, angellina, Godzilla groups>-C4) peralkaline straight or branched chain selected from the group comprising 2,2,2-triptoreline, 3,3,3-cryptosporella and 2,2-deformability group; (C3-C8) - cycloalkyl monosubstituted amino group, and the substitution is made from a group that includes cyclopropyl, TRANS-1,2-dimethylcyclopropane, CIS-1,2-dimethylcyclopropane, cyclobutyl, cyclopentamine, tsiklogeksilnogo group and diastereoisomers and enantiomers mentioned (C3-C8) cycloalkyl monosubstituted amino group; (C4-C10)cycloalkyl alkyl monosubstituted amino group, and the substitution is made from the group comprising (cyclopropyl)methyl, (cyclopropyl) ethyl and (cyclobutyl)methyl group; a (C3-C10)-Alchemilla and Alchemilla monosubstituted amino group, and the substitution is made from a group comprising allyl, proponila, 3-bucinellina, 2-bucinellina (CIS - or TRANS-position) and 2-penttila group; (C7-C10) aralkylamines, and shall be replaced from the group comprising benzyl, 2-phenylethylene, 1-phenylethylene 2-(naphthyl)methyl, 1-(naphthyl)methyl and phenylpropionate group; d is a group is from the group which includes dibutyl, Diisobutyl, di-sec-bucilina and daintily group; symmetrical disubstituted (C6-C14-cycloalkylation, and shall be replaced from the group comprising dicyclopropyl, dicycloverine, Dicyclopentadiene and Dicyclopentadiene group; disubstituted by (C3-C14) alkylamino straight or branched unsymmetrical circuit, which upon substitution, the total number of carbon atoms is not more than 14; unsymmetrical disubstituted (C4-C14)cycloalkylation, which upon substitution, the total number of carbon atoms does not exceed 14; (C2-C8) azacyclopenta and substituted (C2-C8) azacycloheptane group, and substitution is made from the group comprising 4-methylpiperidino, 4-hydroxypiperidine, 4-(hydroxymethyl)piperidino, 4-(aminomethyl)piperidino, CIS-3,4-dimethylpyrimidinol, TRANS-3,4-dimethylpyrimidinol group and diastereoisomers and enantiomers mentioned (C2-C8) azacycloheptane and substituted (C2-C8) azacycloheptane group; substituted 1-ajoxicillin group, and substitution is made from the group comprising 2-(C11-C3) alkylpiperazine, 4-(C1-C3) alkylpiperazine, 2,4-dimethylpiperidine, 4-hydroxypiperidine group, and the enantiomers referred to [1,n]-dietaryguidelines and substituted [1,n]-dietaryguidelines education; 1-asatullayevna and substituted 1-asatullayevna group selected from the group comprising thiomorpholine and 2-(C1-C3) alkylthiomethyl group; (heterocycle) methylaminopropyl selected from the group comprising 2 - or 3-feniletilamina, 2 - or 3-titillating, 2-, 3 - or 4-pyridylmethylamine, 2 - or 5-pyridinemethanol, 2-personalitymanager.tpo, 2-(imidazolyl) methylaminopropyl and substituted (heterocycle) methylaminopropyl (the substitution is made (C1-C6) alkyl group with straight or branched chain);

1,1-substituted Gerasimova selected from the group comprising 1,1-dimethylhydrazine, N-aminopiperidine group and 1,1-diethylhydrazine; (C1-C4) alkoxyamino, and shall be replaced from the group comprising methoxy group, ethoxypropan, n-propoxylate, 1-medicineshoppe, moreover, the substitution is from a group that includes benzyloxy, 2-venlafaxina, 1-venlafaxina, 2-(naphthyl)methoxy group, 1-(naphthyl)methoxy group and phenylpropoxy; [or(C1-C3) acylamide] alkylamino, and shall be replaced from the group comprising 2-(formamido) ethyl, 2-(acetamido)ethyl, 2-(propionamido)ethyl, 2-(acetamido)through 2-(formamido) through the group, and the enantiomers mentioned [or(C1-C3)-acylamide] alkylamino; or (C1-C3) alkoxyalkanols, and shall be replaced from the group comprising 2-methoxyaniline, 2-ethoxyethylene, 2,2-diethoxyaniline, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropionate and 3.3-diethoxypropionate group, and the enantiomers mentioned - or - (C1-C3) alkoxyalkanols;

- or -(C2-C4) hydroxyethylamino selected from the group comprising 3-hydroxiproline and 4-hydroxybutyrate group; or R3and W taken together are selected from the group comprising a group - (CH2)n(R5)N - with n ranging from three to four and group-CH2CH(OH)-CH2(R5)N-, in which R52
-C3) Galiullina group selected from the group comprising trifluoracetyl, 3,3,3-triphosphopyridine and 2,3,3-triphosphopyridine group;

R6is selected from the group comprising hydrogen, (C1-C3) alkyl group with straight or branched chain selected from the group comprising methyl, ethyl, n-sawn or 1-mtilatila group; (C6-C10)aryl group selected from the group comprising phenyl, - naftalina or naftalina group; (C7-C9) kalkilya group, such as benzyl, 1-phenylethylene, 2-phenylethylene or phenylpropionate group; heterocyclic group with five-membered aromatic or saturated ring containing one heteroatom, such as nitrogen, oxygen, sulfur or selenium, optionally having a benzo or pyridoxol condensed with:

< / BR>
such as pyrrolidine, N-methylindoline, indayla, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolidinyl, tetrahydrofuranyl, furazilina, benzofuranyl, tetrahydrothiophene, thienyl, benzothiazoline or selenazoline group; or a five-membered aromatic ring containing generowanie with:

< / BR>
such as imidazolidine, pyrazolidine, benzimidazolyl, oxazolidine, benzoxazolinone, indazolinone, thiazolidine, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b] Peregrina or pyridylmethylene group; or the group -(CH2)nCOOR8with a value of n ranging from zero to four, where R8is selected from the group comprising hydrogen; (C1-C3) alkyl group with straight or branched chain selected from the group comprising methyl, ethyl, n-sawn or 1-mtilatila group; or (C6-C10) aryl group selected from the group comprising phenyl, - naftalina or naftalina group;

R7is selected from the group comprising hydrogen; (C1-C3) alkyl group with straight or branched chain selected from the group comprising methyl, ethyl, n-sawn or 1-mtilatila group; (C6-C10) aryl group selected from the group comprising phenyl, - naftalina or naftalina group; (C7-C9) kalkilya group, such as benzyl, 1-phenylethylene, 2-phenylethylene or phenylpropionate group; heterocyclic group with five-membered aromatic or saturated is - or pyridoxol, condensed from:

< / BR>
such as pyrrolidine, N-methylindoline, indayla, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolidinone, tetrahydrofuranyl, furazilina, benzofuranyl, tetrahydrothiophene, thienyl, benzothiazoline or selenazoline group; or a five-membered aromatic ring containing two heteroatoms such as nitrogen, oxygen, sulfur or selenium, optionally having a benzo or pyridoxol condensed with:

< / BR>
such as imidazolidine, pyrazolidine, benzimidazolyl, oxazolidine, benzoxazolinone, indazolinone, thiazolidine, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b] Peregrina or pyridylmethylene; or the group -(CH2)nCOOR8with a value of n ranging from zero to four, where R8is selected from the group comprising hydrogen; (C1-C3) alkyl group with straight or branched chain selected from the group comprising methyl, ethyl, n-sawn or 1-methyl group; or (C6-C10)aryl group selected from the group comprising phenyl, - naftalina or naftalina group; with the proviso that R6and R7cannot simultaneously be hydrogen; or R6and R2)nwith the value of n is zero or one, -NH, -N(C1-C3) an alkyl group (straight or branched chain), -N(C1-C4) alkoxygroup, oxygen, sulfur or substituted related education, selected from the group which includes (L or D) Proline, ethyl (L or D)prolinate have been obtained, morpholine, pyrrolidine or piperidine; and the pharmacologically acceptable organic and inorganic salts and metal complexes.

The compounds of special interest includes compounds of formulas I and II, which

R is a halogen selected from the group that includes bromine, chlorine and iodine; or R is a group-NR1R2and, when R is a group-NR1R2and R1is a methyl or ethyl group, then

R2is a methyl or ethyl group;

R3is hydrogen;

R4is selected from hydrogen and (C1-C2) alkyl group selected from methyl and ethyl groups;

when R3does not match the R4, stereochemical state of the asymmetric carbon (i.e. the carbon bearing the Deputy W) may be either the racemate (DL) or the individual enantiomers (L or D);

W is selected from the group which includes (C7the categories are heptylene, anjilina, Danilina, decile, angellina, Godzilla group and diastereoisomers and enantiomers mentioned branched alkyl monosubstituted amino group; (C2) peralkaline selected from the group comprising 2,2,2-triptoreline and 3,3,3-cryptosporella group; (C3-C8) cycloalkyl monosubstituted amino group, and the substitution is made from a group that includes cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo group and diastereoisomers and enantiomers mentioned (C3-C8) cycloalkyl monosubstituted amino group; [(C4-C5) cycloalkyl] alkyl monosubstituted amino group, and the substitution is made from the group comprising (cyclopropyl)methyl and (cyclopropyl)ethyl group; a (C3-C4) Alchemilla and Alchemilla monosubstituted amino group, and the substitution is made from a group comprising allyl and proponila group; (C2-C7)azacyclopenta and substituted (C2-C7)azacycloheptane group, and substitution is made from the group comprising 4-methylpiperidine, 4-hydroxypiperidine and 4-(hydroxymethyl) piperidine; substituted 1-isoxazolidine gra; [1, n] -dietetically and substituted [1,n]-dietetically group selected from piperazinilnom and 4-(C1-C3) alkylpiperidines group; 1-asatullayevna and substituted 1-asatullayevna group selected from thiomorpholine and 2-(C1-C3) alkylthiomethyl group; (heterocycle) methylaminopropyl selected from the group comprising 2 - or 3-titillating and 2-, 3 - or 4-pyridylmethylamine; 1,1-disubstituted Gerasimova selected from 1,1-dimethylhydrazinium and N-aminopiperidine group; [or(C1-C3)acylamide] alkylamino with substitution produced from 2-(acetamido) ethyl group; or(C1-C3) alkoxyalkanols, and shall be replaced from the group comprising 2-methoxyaniline, 2-accosiation, 2,2-diethoxyaniline, 2-methoxypropyl and 3-methoxypropyl group; - or -(C2-C4) hydroxyethylamino selected from 4-hydroxybutanal and 3-hydroxypropyl group; or R3and W taken together are selected from the group -(CH2)n(R5) - with the value of n is equal to three, and R5is selected from hydrogen and trifluoracetyl group;

R6is selected from the group, which includes methyl, ethyl, n-sawn or 1-mtilatila group;

R7is selected from the group comprising hydrogen; (C1-C3) alkyl group with straight or branched chain selected from the group comprising methyl, ethyl, n-sawn or 1-mtilatila group; with the proviso that R6and R7at the same time cannot represent hydrogen; or R6and R7taken together, represent a group -(CH2)2B(CH2)2-, in which B is selected from the group comprising (CH2)nwith the value of n is zero or one, -NH, -N(C1-C3) an alkyl group (straight or branched chain), -N(C1-C4) alkoxygroup, oxygen, sulfur or substituted related education, selected from the group which includes (L or D)Proline, ethyl (L or D) prolinate have been obtained, morpholine, pyrrolidine or piperidine; and the pharmacologically acceptable organic and inorganic salts or metal complexes.

In addition, under the present invention also includes compounds which are useful as intermediates in obtaining the compounds corresponding to formulas I and II. Such intermediate compounds include soetigna to five; X is a halogen selected from the group which includes bromine, chlorine, fluorine or iodine;

R is a halogen selected from the group, in which violet bromine, chlorine, fluorine and iodine; or R is a group-NR1R2and when R-NR1R2and R1is hydrogen, then

R2is methyl, ethyl, n-through, 1-mtilatila, n-bucilina, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethylene group;

and, when R1is a methyl or ethyl group,

R2is methyl, ethyl, n-through, 1-mtilatila, n-bucilina, 1-methylpropyl or 2-methylpropyl group; and when R1- n-through the group,

R2- n-through, 1-mtilatila, n-bucilina, 1-methylpropyl or 2-methylpropyl group;

and, when R1- 1-mtilatila group,

R2- n-bucilina, 1-methylpropyl or 2-methylpropyl group;

and, when R1- n-bucilina group,

R2- n-bucilina, 1-methylpropyl or 2-methylpropyl group;

and, when R1- methylpropyl group,

R2- 2-methylpropyl group;

R3is selected from the group comprising hydrogen, (C4-C8) alkyl group with straight or branched chain selected from the group UB>4) alkyl group selected from the group comprising mercaptomerin, - mercaptoethylamine, - mercapto-1-mtilatila and - mercaptopropyl group; - hydroxy-(C1-C4) alkyl group selected from the group comprising herasimenia, - hydroxyethylene, - hydroxy-1-mtilatila and - hydroxiproline group; carboxyl-(C1-C8) alkyl group; a (C6-C10) aryl group selected from the group comprising phenyl, - naftalina and - naftalina group; a substituted (C6-C10) aryl group (substitution is made from the group comprising hydroxy-group, halogen, (C1-C4) alkoxygroup, trihalo (C1-C3) alkyl group, a nitrogroup, amino, cyano, (C1-C4) alkoxycarbonyl group, (C1-C3) alkylamino and carboxypropyl); (C7-C9) kalkilya group selected from the group comprising benzyl, 1-phenylethylene, 2-phenylethylene and phenylpropionate group; a substituted (C7-C9) kalkilya group (substitution is from a group that includes holograph, (C1-C4) alkyl group, a nitrogroup, a hydroxy-group, amino group, mono - or di is Honiley group, cyano and carboxypropyl);

R4is selected from hydrogen and (C1-C6) alkyl group selected from the group comprising methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, pentilla and exilda group;

when R3does not meet R4, stereochemical state of the asymmetric carbon (i.e. the carbon bearing the Deputy W) may respond to either the racemate (DL) or the individual enantiomers (L or D); and the pharmacologically acceptable organic and inorganic salts or metal complexes.

Preferred compounds are compounds with formula III, in which

Y is selected from (CH2)nX with the value of n in the range from zero to five, where X is a halogen selected from the group that includes bromine, chlorine, fluorine or iodine;

R is a halogen selected from the group that includes bromine, chlorine, fluorine and iodine; or R is a group-NR1R2and, when R is a group-NR1R2and R1is hydrogen,

R2is methyl, ethyl, n-through, 1-mtilatila, n-bucilina, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethylene group;

and, when R1is a methyl or ethyl group,

R2is methyl, ethyl, n-PR is camping from the group which includes hydrogen; (C4-C8) alkyl group with straight or branched chain selected from the group comprising bucilina, isobutylene, pentilla, hexeline, Reptilia and anjilina group; hydroxy (C1-C4) alkyl group selected from the group comprising hydroxymethylene, - hydroxyethylene, - hydroxy-1-mtilatila and - hydroxiproline group; carboxyl-(C1-C8) alkyl group; a (C6-C10)aryl group selected from the group comprising phenyl, - naftalina and - naftalina group; a substituted (C6-C10) aryl group (substitution is made from the group comprising hydroxy-group, halogen, (C1-C4) alkoxygroup, (C1-C4) alkoxycarbonyl group and carboxypropyl); (C7-C9) kalkilya group selected from the group comprising benzyl, 1-phenylethylene, 2-phenylethylene and phenylpropionate group; a substituted (C7-C9) kalkilya group (substitution is from a group that includes holograph, (C1-C4) alkyl group, (C1-C4) alkoxygroup, (C1-C4) alkylsulfonyl group, cyano, (C1-C4) alkyls McIlroy group, selected from the group comprising methyl, ethyl, sawn, ISO-propyl, bucilina and isobutylene group; when R3does not match the R4, stereochemical state of the asymmetric carbon (i.e. the carbon bearing the Deputy W) may respond to either the racemate (DL) or the individual enantiomers (L or D); and the pharmacologically acceptable organic and inorganic salts and metal complexes.

Especially preferred compounds are compounds with formula III, in which

Y is selected from (CH2)nX with the value of n in the range from zero to five, where X is a halogen selected from the group that includes bromine, chlorine, fluorine or iodine;

R is a halogen selected from the group that includes bromine, chlorine, fluorine and iodine; or R is a group-NR1R2and, when R is a group-NR1R2and R1is hydrogen,

R2is methyl, ethyl, n-through, 1-mtilatila, n-bucilina, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethylene group;

and, when R1is a methyl or ethyl group,

R2is methyl, ethyl, n-through, 1-mtilatila, n-bucilina, 1-methylpropyl or 2-methylpropyl group;

R3is selected from the group KPI, which includes bucilina, isobutylene, Petelina and exilda group; (C6-C10)aryl group selected from the group comprising phenyl, - naftalina and/ naftalina group; (C7-C9) kalkilya group selected from the group comprising benzyl, 1-phenylethylene, 2-phenylethylene and phenylpropionate group;

R4is selected from hydrogen and (C1-C3) alkyl groups comprising methyl, ethyl, sawn and ISO-propyl group;

when R3does not match the R4, stereochemical state of the asymmetric carbon (i.e. the carbon bearing the Deputy W) may respond to either the racemate (DL) or the individual enantiomers (L or D); and the pharmacologically acceptable organic and inorganic salts or metal complexes.

Compounds of particular interest are compounds of formula III, in which

Y is selected from (CH2)nX with the value of n in the range from zero to five, where X is a halogen selected from the group that includes bromine, chlorine, fluorine or iodine;

R is a halogen selected from the group that includes bromine, chlorine or iodine; or R is a group-NR1R2and, when R is a group-NR1R2and R1<
R4is selected from hydrogen and (C1-C2) alkyl group selected from methyl and ethyl groups;

when R3does not match the R4, stereochemical state of the asymmetric carbon (i.e. the carbon bearing the Deputy W) may respond to either the racemate (DL) or the individual enantiomers (L or D); and the pharmacologically acceptable organic and inorganic salts or metal complexes.

Description of the preferred embodiments

Previously unknown connections that meets the present invention can be easily obtained by the following schema.

The preferred way to obtain 7-(substituted)-9-[(substituted - glycyl)amido] -6-dimethyl-6-desoximetasone or salts of mineral acids (3) is shown in scheme 1. In this way, use the usual intermediate compounds that can be easily obtained by the interaction of industrially produced Galiullina of Gulidov with the formula

< / BR>
where

Y, R3and R4are as defined above, and Q is halogen selected from the group that includes bromine, chlorine, iodine and fluorine, with 9-amino-7-(substituted)-6-dimethyl-6 - desoximetasone or its salt of the mineral acid is oxitetraciclina straight or branched chain, or salts of mineral acids (2). The above intermediate compounds, namely, 9-[(haloacyl)amido]-7-(substituted)-6-dimethyl-6-desoximetasone or salts of mineral acids (2), interact with a number of nucleophilic compounds, particularly amines having the formula WH, where W is as it was defined previously, resulting in the formation of new 7-(substituted)-9-[(substituted - glycyl)amido] -7-(substituted)-6-dimethyl-6-desoximetasone or salts of mineral acids (3) complying with the present invention.

< / BR>
In accordance with the scheme of 1.9-amino-7-(substituted)-6-dimethyl-6 - detoxification or its salt of mineral acid (I) is mixed with:

a) a polar aprotic solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidone, hereinafter called DMPU, hexamethylphosphoramide, hereinafter called GMFA, dimethylformamide, dimethylacetamide, N-organic, 1,2-dimethoxyethane, or similar compounds;

b) an inert solvent, such as acetonitrile, methylene chloride, tetrahydrofuran, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachlorethane, simple diethyl ether, simple tert-butyl methyl ether, simple, isopropyl ether, or similar compounds;

C) the basis of the ylamine, the cesium carbonate, lithium carbonate or equivalent bicarbonate; and

g) Galiullina the halide with a straight or branched chain with the formula:

< / BR>
where Y, R3, R4and Q are as defined above, such as bromide bromoacetyl, chloroacetyl chloride, bromide, 2-bromopropionyl or similar; holograph Y and halide Q u galilleo halide can be the same or different Halogens selected from the group that includes bromine, chlorine, iodine and fluorine; Y is a group (CH2)nX with the value of n in the range from zero to five, where X is halogen;

d) for from 0.5 to 5 h at room temperature with heating to a temperature interaction in a vessel with reflux condenser, resulting in the formation of the corresponding 9-[(haloacyl)amido]-7-(substituted)-6-demethyl-6 - desoximetasone (2) or its salt of the mineral acid.

Intermediate connection, namely 9-[(haloacyl)amido]-7 - substituted)-6-dimethyl-6-detoxification or its salt of mineral acid (2), treated in an inert atmosphere of helium, argon or nitrogen

(a) nucleophilic compound WH, such as amine, substituted amine, or similar connection, such as methylamine, dimethylamine is Kim as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidone (DMPU), hexamethylphosphoramide (HMPA), dimethylformamide, dimethylacetamide, N-organic or 1,2-dimethoxyethane;

C) for from 0.5 to 2 h at room temperature or at the temperature of heating in a vessel under reflux, to obtain the desired 7-(substituted)-9-[(substituted glycyl)amido]-6-dimethyl-6-detoxification (3) or its salt of the mineral acid.

Scheme II

< / BR>
In accordance with scheme II, compounds of formula 3 are N-alkylated in the presence of formaldehyde and a primary amine such as methylamine, ethylamine, benzylamine, methylglycine, (L - or D-)alanine, (L or D)-lysine, or their related compounds substituted or secondary amine, such as morpholine, pyrrolidine, piperidine, or related substituted compounds, resulting in a corresponding adduct Mannich bases (Mannich) 4.

7-(substituted)-9-[(substituted-glycyl)amido] -6-dimethyl-6 - desoximetasone can be obtained in the form of complexes of metals such as aluminum, calcium, iron, magnesium, manganese, and in the form of complex salts, inorganic and organic salts and the corresponding adducts grounds manniche, what methods they use, known specialitem in this field of technology it is well known that an appropriate salt form is selected based on the physical and chemical stability, flowability, hygroscopicity and solubility. It is desirable that the 7-(substituted)-9-[(substituted-glycyl)amido]-6-demethyl-6 - desoximetasone was obtained in the form of inorganic salts, such as chloride, bramina, iodine, phosphate, nitrate or sulfate, or organic salts such as acetate, benzoate, citrate, cysteinate, or in the form of salts other amino acids, such as fumaric, picolata, Malatya, succinate, tartrate, alkylsulfonate or arylsulfonate. Depending on the stoichiometry of the used acid salt formation occurs by interaction with the C(4)-dimethylaminopropoxy (1 equivalent acid) or C(4)-dimethylaminopropoxy and W-band (2 equivalents of acid). These salts suitable for oral and parenteral administration.

Some compounds described in the above schemes, have centers of asymmetry at the carbon that bears the Deputy W. These compounds can, therefore, exist in at least two (2) stereoisomeric forms. The present invention extends to a racemic mixture of stereoisomers and n is Messi with stereoisomers in any ratio of enantiomers. The true configuration of any connection can be established method to conventional x-ray crystallography.

Stereochemical centers, existing tetracycline education (i.e., C-4, C-4a, C-5a and C-12a), remain intact during all interactions.

Biological activity

Methods for antimicrobial evaluation in vitro (table. 1)

Minimum inhibitory concentration (MIC), i.e. the lowest concentration of antibiotic at which the growth inhibition of the test organism is determined by agar dilution method using 0.1 ml II agar Mueller-Hinton (Muller-Hinton II agar) (Baltimore biological laboratories) in the calculation of the recess. Were used Inculata density value (1-5)105colony forming units per 1 ml of the antibiotic concentration range 32 - of 0.004 µg/ml Minimum inhibitory concentration was determined after incubation of the plates for 18 h at 35oC in an incubator with forced air circulation. The test organisms were represented by strains that are sensitive to tetracycline, and genetically established strains, resistacne to tetracycline due to the inability to link tank is and in vitro free cell protein translation system, that was done using extracts of strain MRE culture of E. coli (sensitive to tetracycline) and derived from strain MRE containing tetM-determinants; the system was developed based on the literature methods (J. M. Pratt, Coupled reduced-translation in Prokaryotic Cell-free Systems, reduced and Translation, a Practical Approach, (B. D. Hames and S. J. Higgins. eds) p. 179 - 209, IRL Press, Oxford-Washington, 1984).

Using the system described above, the tetracycline compounds conforming to the present invention were tested for their ability to inhibit protein synthesis in vitro. In short, in each case 10 μl reaction mixture contained S30-extract (full extract) prepared from either sensitive to tetracycline cells or from isogenic resistant to tetracycline (tetM) strain, low-molecular components necessary for the occurrence of transcription and translation (i.e., ATP and GTP), a mixture of 19 amino acids (without methionine), methionine labeled in the form of sulfur-35, DNA template (either pBP322 or p C119) and either dimethylsulfoxide (DMSO) (control experiment), or previously unknown tetracycline compound, subjected to testing ("novel TC"), which was dissolved in dimethyl sulfoxide.

The reaction mixture was incubated for 30 min at 37oC. Time otschityvaniya mixture, and it was mixed with 0.5 ml of 1 n sodium hydroxide solution, which was necessary for the destruction of RNA and tRNA. Was added 2 ml of 25% trilocana acid, and the mixture is incubated at room temperature for 15 minutes the Substance deposited under the influence of trichloroacetic acid, collected on GF/C filters Watman (Whatman) and washed with a solution of 10% trichloroacetic acid. The filters were dried and the retained radioactivity is caused by the capture of 35S-methionine polypeptides, were measured using standard liquid scintillation techniques.

The percentage inhibition of protein synthesis was determined by the formula

< / BR>
Antibacterial evaluation in vivo.

therapeutic action of tetracyclines has established in relation to acute detailed infection, for which we used a strain Smith (Smith) culture Staphulococcus aureus (susceptible to tetracycline). Male rat species-line CD-1 (Charles river laboratories) weighing 20 2 g did intraperitoneally injection of bacteria suspended in a porcine mucous secretion) in a quantity sufficient to kill the untreated control specimens for 24 - 48 hours Antibacterial agent contained in 0.5 ml of 0.2% aqueous agar, were administered subcutaneously or orally for one injection. At each dose level were treated five mice. To calculate half of the effective dose (ED50used the coefficients of the 7-day survival rates found in three separate tests.

Test results

The claimed connection detect antibacterial activity against a wide spectrum susceptible to tetracycline and resistant gram-positive and gram-negative bacteria, especially against strains cultures of E. coli, S. aureus and E. faecalis containing tetM - tetD - resistant determinants, and cultures of E. coli containing tetB and tetD resistant determinants. It should be noted compounds D, G, and K listed in table. I find that a very high activity in vitro against resistant to tetracycline strains containing tetM-resistant determinant (such as S. aureus VBMS 88-5, S. aureus VBMDS 90-1 and 90-2, E. coli VBMS 89-1 and 90-4), and resistant to tetracycline strains containing tetB-resistant determinant (such as E. coli VBMS 88-1 and E. coli TNIOC tetB). These compounds also possess good activity against E. coli tetA, E. coli tetC and E. coli tetD and is equally effective as minocycline, against susceptible strains and surpass minocycline in respect of a number of recently wideley H was investigated in vitro for their ability to inhibit protein synthesis, occurring or wild-type, or tetM-protected ribosomes, which used collaborative transcription and translation system. Found that all compounds effectively inhibit protein synthesis occurring in the wild-type ribosomes, with equivalent levels of activity. Minocycline does not possess the ability to inhibit protein synthesis occurring in the tetM-protected ribosomes. In contrast compounds B, C, D, G, and H are effective in inhibition of protein synthesis occurring on tetM-protected ribosomes (table. II).

Compounds B, C, D, G, and H reversibly binds to its target (the ribosome), since bacterial growth is resumed when the join is removed from the cultures by washing of the body. Therefore, it seems that the ability of these compounds to inhibit bacterial growth is a direct result of their ability to inhibit protein synthesis at the ribosomal level.

The potency of the compound G against susceptible to tetracycline organisms also demonstrated in vivo in animals, investirovnny strain Smith culture of S. aureus, the values of the ED50lying in the region of 1-2 mg/kg when EXT is fair the effectiveness of compounds D, G and K demonstrates in vitro activity against inhibition of isogenic strains that have cloned resistant determinants, such as tetM and tetB (PL. I) and inhibiting protein synthesis tetM-ribosomes (table. II).

As you can see from the table. I and II, the compounds conforming to the present invention can also be used to prevent and impact on the course of important veterinary diseases, such as diarrhoea, a disease caused by infection in the urinary tract, diseases caused by exposure to infections on the skin and its condition, a disease associated with infection in the ears, nose and throat, diseases caused wound infections, mastitis and the like diseases.

The description of the compounds contained in tables

A [7S-(alpha, 10a alpha)]-N-[9-(aminocarbonyl)-4,7-bis(dimethylamino)- 5,5 a, 6, 6A, 7,10,10 a,12 octahydro-1,8,10 a,11 tetrahydroxy-10,12 - dioxo-2-naphthalenyl]-1-(TRIFLUOROACETYL)-2-pyrrolidinecarboxamido

B [4S-(4 alpha, 12a alpha)] -4,7-bis(dimethylamino)-1,4,4 a, 5,5 a, 6,11,12 n-octahydro-3,10,12,12 a-tetrahydroxy-9-[[[(2 - methoxyethyl)amino] acetyl]amino]-1,11-dioxo-2 - naphthacenecarboxamide

C [4S-(alpha, 12a alpha)]-9-[[[(2,2-diatexite)amino] acetyl]amino] -4,7-bis(dimethy the alpha, 12a alpha)]-4,7-bis(dimethylamino)-1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11-dioxo - 9-[[(2-propylamino)acetyl]amino]-2 - naphthacenecarboxamide

E [4S-(alpha, 12a alpha)]-4,7-bis(dimethylamino)-1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11-dioxo 9-[[[(2-pyridinylmethyl)amino]acetyl]amino]-2 - naphthacenecarboxamide

F [7S-(7-alpha, 10a alpha)]-N-[9-(aminocarbonyl)-4,7-bis(dimethylamino)-5,5 a,6,6A, 7,10,10 a,12 octahydro-1,8,10 a,11 tetrahydroxy-10,12-dioxo-2 - naphthalenyl]-4-dimorpholinyldiethyl

G [7S-(alpha, 10a alpha)]-N-[9-(aminocarbonyl)-4,7-bis(dimethylamino)-5,5 a,6,6A, 7,10,10 a,12 octahydro-1,8,10 a,11 tetrahydroxy-10,12-dioxo-2 - naphthalenyl]-4-methyl-1-piperidinemethanol

H [4S-(alpha, 12a alpha)]-4,7-bis(dimethylamino)-1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-9-[[[(3 - methoxypropyl)amino] acetyl]amino]-1,11-dioxo-2 - naphthacenecarboxamide

I 7[7S-(alpha, 10a alpha)]-N-[9-(aminocarbonyl)-4,7-bis (dimethylamino)-5,5 a, 6, 6A, 7,10,10 a, 12 octahydro-1,8,10 a,11 tetrahydroxy-10,12-dioxo-2-naphthalenyl]-4-methyl-1 - piperazineethanesulfonic

J [4S-(4 alpha, 12a alpha)]-4,7-bis(dimethylamino)-9- [[(heptylamine)acetyl] amino] -1,4,4 a, 5,5 a,6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11-dioxo-2 - naphthacenecarboxamide

L [4S-(4 alpha, 12a alpha)] -4,7-bis(dimethylamino)-1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11-dioxo-9- [[(undecillion)acetyl]amino]-2-naphthacenecarboxamide

M [4S-(4 alpha, 12a alpha)]-9-[(bromoacetyl)amino]-4,7-bis (dimethylamino)-1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12,12 a - tetrahydroxy/1,11-dioxo-2-naphthacenecarboxamide

N tetracycline

O minocycline

P [4S-(alpha, 12a alpha)]-4,7-bis(dimethylamino)-1,4,4 a,5,5 a,6,11,12 a-octahydro - 3,10,12,12 a-tetrahydroxy-9-[[[(2-hydroxyethyl)amino] acetyl] amino]-1,11-dioxo-2-naphthacenecarboxamide

Q [4S-(4 alpha, 12a alpha)] -4,7-bis(dimethylamino)- 1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-9-[[[(2 - hydroxyethyl)methylamino]acetyl]amino]-1,11-dioxo-2 - naphthacenecarboxamide

R [4S-(4 alpha, 12a alpha)]-4,7-bis(dimethyl-4-amino-1-amino) 1,4,4 a, 5,5 a,6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-9-[[[(4- (hydroxybutyl)amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide

S [4S-(4 alpha, 12a alpha)] -4,7-bis(dimethylamino)- 1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11 - dioxo-9-[[[(2,2,2-triptorelin)amino]acetyl]amino]-2-naphthacenecarboxamide

T [4S-(alpha, 12a alpha)] -4,7-bis(dimethylamino)-9- [[[(2-foradil)amino] acetyl] amino]-1,4,4 a,5,5 a,6,11,12 a - octahydro-3,10,12,12 a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide
V is [4S-(4 alpha, 12a alpha)] -4,7-bis(dimethylamino) -1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy - 9-[[[methyl-2-propylamino] acetyl]amino]-1,11-dioxo-2 - naphthacenecarboxamide

W [4S-(4 alpha, 12a alpha)]-4,7-bis(dimethylamino) 1,4,4 a,5,5 a, 6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy - hydroxy-1,11-dioxo-9-[[(1-piperidylamine)acetyl]amino]-2 - naphthacenecarboxamide

X [4S-(4 alpha, 12a alpha)]-4,7-bis(dimethylamino) 1,4,4 a,5,5 a, 6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy - 1,11-dioxo-9-[[[(phenylmethoxy)amino]acetyl]amino]-2 - naphthacenecarboxamide.

When using compounds as antibacterial agents, they can be connected with one or more pharmaceutically acceptable carriers, such as solvents, diluents and the like substances, and can be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% suspending agents, syrups containing, for example, about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and similar substances, or parenterally in the form of sterile injectively solutions or suspensions containing from about 0.05 to 5% suspending substances in the 90% of the active ingredient in combination with a carrier, the content of which by weight is often about 5 to 60%.

Now the current number of connections in the range from 2.0 mg per 1 kg of body weight and up to 100.0 mg per 1 kg of body weight should be administered one to five times in any typical route of administration, including, but not limited to, oral, parenteral (including subcutaneous, intravenous, intramuscular, intrasternal injection or injection by infusion), local or rectal, when the formulation of the composition for a single reception, containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and fillers. However, it should be understood that the specific dose and frequency of intake of a patient may vary and depend on various factors including the activity of specific applied compounds, the metabolic stability and length of action of this drug, the age, body weight, General condition, sex, diet, mode and time of administration, excretion rate, combination of drugs, the severity of this condition and the nature of therapy.

These active compounds may be administered orally as well as intravenously, intramuscular and the practical cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-toxic surfactants and edible oils such as corn, peanut and sesame oil, which are used taking into account the nature of the active ingredient and the particular form of administration. Can be successfully introduced adjuvants commonly used in the preparation of pharmaceutical compositions, such as odorous substances, colorants, preservatives and antioxidants, such as vitamin E, ascorbic acid, 2,6-di-tert-butyl-p-cresol (BHT) and tert-butyl-4-methoxyphenol (BHA).

The preferred pharmaceutical compositions from the standpoint of ease of preparation and introduction are solid compositions, particularly tablets or capsules filled with a solid or liquid substance. Oral route of administration of the compounds is preferred.

These active compounds may be introduced parenterally, or IPR. Solutions or suspensions of these active compounds, such as free base or pharmacologically acceptable salt can be prepared glycol, liquid, polyethylene glycols and mixtures thereof in oils is croorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders intended for instant preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that ensures the ease of sampling syringe. The form must be stable under conditions of manufacture and storage and must be protected from pollution impact of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils.

The invention will be more fully described with the following specific examples which are not intended to limit the framework of the invention.

Example 1

[4S-(alpha, 12a alpha)]-9-[(chloroacetyl)amino]-4,7-bis (dimethylamino)-1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12,12 a - tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

To a room temperature solution containing 0,334 g of 9-amino-4,7-bis(dimethylamine, DMPU, and 2 ml of acetonitrile, was added 0,318 g of sodium carbonate. The mixture was stirred for 5 min, then was added 0,068 g chloroacetanilide. The reaction mixture was stirred for 30 min, filtered, and the filtrate was added dropwise to 100 ml of a simple diethyl ether containing 1 ml of 1M hydrochloric acid in the form of a solution in a simple diethyl ether. The resulting solid is collected and dried, resulting in a received 0,340 g of the desired intermediate. Method of mass spectrometry (fast atom bombardment) found that the ratio of mass-to-charge m/z is 549 (M + H molecular formation and hydrogen)).

Example 2

[4S-(alpha, 12a alpha)]-9-[(bromoacetyl)amido]-4,7-bis (dimethylamino)-1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12,12 a - tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The named compound was prepared according to the method of example 1, using of 6.68 g of 9-amino-4,7-bis(dimethylamino)-6-dimethyl-6 - desoxycorticosterone, 50 ml of 1,3-dimethyl-3,4,5,6 - tetrahydro-2(1H)pyrimidinone, 30 ml of acetonitrile, of 6.68 g of sodium carbonate and 0,215 g of methyl bromacetyl. Got 5,72 g of the desired intermediate. Method of mass spectrometry (fast atom bombardment) S="ptx2">

Example 3

[4S-(alpha,12a alpha)]-9-[(2-bromo-1-oxopropyl)amino]-4,7 - bis(dimethylamino)-1,4,4 a, 5,5 a, 6,11,12 a-octahydro-3,10,12,12 a - tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The named compound was prepared according to the method of example 1, using a 1.00 g of 9-amino-4,7-bis(dimethylamino)-6-dimethyl-6 - desoxycorticosterone, 1.0 g of sodium carbonate and 0,648 g of methyl 2-bromopropionyl, resulting received 0,981 g of the desired product. Method of mass spectrometry (fast atom bombardment) found that the ratio of mass-to-charge m/z is 607 (M + H molecular formation, the retaining hydrogen)).

Example 4

[4S-(alpha, 12a alpha)]-9-[(4-bromo-1-oxobutyl)amino]- 4,7-bis(dimethylamino)-1,4,4 a, 5,5 a, 6,11,12 a-octahydro - 3,10,12,12 a-tetrahydroxy-1,11-dioxo-2 - naphthacenecarboxamide

The named compound was prepared according to the method of example 1, using of 1.34 g of 9-amino-4,7-bis(dimethylamino)-6-dimethyl-6 - desoxycorticosterone, 1.3 g of sodium carbonate, 24 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone, 8 ml of acetonitrile and 0,389 g chloride 4-bromobutyryl, resulting received 1.45 g of the desired product.

Example 5

[7S-(7 alpha, 10a alpha)]-N-[9-(aminocarbonyl)-4,7-bis (dimethylamino)-5,5 a, 6,7,10 a, 12-octaved the Titled compound was prepared according to the method of example 1, using 0,334 g of 9-amino-4,7-bis(dimethylamino)-6-dimethyl-6 - desoxycorticosterone, 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone, 2 ml of acetonitrile, 0.34 g of sodium carbonate and 7.5 ml of 0.1 M chloride (S)-(-)-N-(TRIFLUOROACETYL) prolyl, resulting received 0,292 g of the desired product. Method of mass spectrometry (fast atom bombardment) found that the ratio of mass-to-charge m/z is 666 (M + H molecular formation, the retaining hydrogen)).

Example 6

[4S-(alpha, 12a alpha)]-9-[[[(cyclopropylmethyl)amino]- acetyl]-amino] -4,7-bis(dimethylamino)-1,4,4 a, 5,5 a, 6,11,12 a - octahydro-3,10,12,12 a-tetrahydroxy-1,11-dioxo-2 - naphthacenecarboxamide

A mixture containing 0.20 g of product from example 2, 0.50 g (aminomethyl) cyclopropane and 5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H) pyrimidinone, was stirred in an argon atmosphere at room temperature for 1 h, Excess amine was removed in vacuo, and the residue was diluted with a small volume of methyl alcohol. The diluted reaction solution was added dropwise to a simple mixture of diethyl ether and 5 ml of 2-propanol. Hydrochloric acid with a concentration of 1 M in diethyl simple ether, was added before the formation of solids. Result spectrometry (fast atom bombardment) installed, what is the ratio of mass-to-charge m/z is 584 (M + H molecular formation, the retaining hydrogen)).

Basically the methods described above in example 6, was prepared compounds that meet this invention listed below in examples 7 to 16 cm table. 3).

Example 7

[4S-(alpha, alpha 12a)]-9-[[[(2,2-diatexite)amino]acetyl]- amino]-4,7-bis(dimethylamino)1,4,4 a, 5,5 a, 6,11,12 a-octahydro - 3,10,12,12 a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

Example 8

[4S-(alpha, 12a alpha)]-4,7-bis(dimethylamino)-1,4,4 a,5,5 a,6,11,12 a-octahydro - 3,10,12,12 a-tetrahydroxy-9-[[[2-(methoxyethyl)amino] acetyl]amino]- 1,11-dioxo-2-naphthacenecarboxamide

Example 9

[4S-(alpha, 12a alpha)]-4,7-bis(dimethylamino)-1,4,4 a,5,5 a, 6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11-dioxo-9- [[(2-propylamino)acetyl]amino]-2-naphthacenecarboxamide

Example 10

[4S-(alpha, 12a alpha)]-4,7-bis(dimethylamino)-1,4 a,4,5, 5a,6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-9-[[[(3 - methoxypropyl)amino] acetyl] amino]-1,11-dioxo-2 - naphthacenecarboxamide

Example 11

[7S-(alpha, 10a alpha)]-N-[9-(aminocarbonyl)-4,7-bis (dimethylamino)-5,5 a, 6, 6A, 7,10,10 a,12 octahydro-1,8,10 a,11 tetrahydroxy-10,12-dioxo-2-naphthalenyl]-4 - thiomorpholine is a 12-octahydro-1,8,10 a,11 tetrahydroxy-10,12-dioxo-2-naphthalenyl]-4-methyl-1 - piperidinemethanol

Example 13

[7S-(alpha, 10a alpha)]-N-[9-(aminocarbonyl)-4,7-bis (dimethylamino)-5,5 a, 6, 6A, 7,10,10 a,12 octahydro-1,8,10 a,11 tetrahydroxy-10,12-dioxo-2-naphthalenyl]-4-methyl-1 - piperazineethanesulfonic

Example 14

[4S-(alpha, 12a alpha)] -4,7-bis(dimethylamino)-9-[[(heptyl - amino)acetyl] amino] -1,4,4 a, 5,5 a,6,11,12 a-octahydro-3,10,12,12 a - tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

Example 15

[4S-(4 alpha, 12a alpha)]-4,7-bis(dimethylamino)- 1,4,4 a,5,5 a,6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11 - dioxo-9-[[(undecillion)acetyl] amino]-2 - naphthacenecarboxamide

Example 16

[4S-(4 alpha, 12a alpha)]-4,7-bis(dimethylamino)- 1,4,4 a,5,5 a,6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11 - dioxo-9-[[[(2-pyridinylmethyl)amino]acetyl]amido]-2 - naphthacenecarboxamide

Example 17

[4S-(alpha, 12a alpha)] -4,7-bis(dimethylamino)-1,4,4 a,5,5 a,6,11,12 a-octahydro - 3,10,12,112 a-tetrahydroxy-9-[[[(2-hydroxyethyl)amino] acetyl] amino]- 1,11-dioxo-2-naphthacenecarboxamide

To a solution containing 0.10 g of product from example 7A, which was in 2 ml of 1,3-dimethyl-2-imidazolidinone added to 0.70 ml of 2-amino-1-ethanol. The solution was stirred at room temperature for 20 min, was added to 100 ml of a simple diethyl ether, and reii (fast atom bombardment) installed, what is the ratio of mass-to-charge m/z is 574 (M+ + H (molecular formation, the retaining hydrogen)). Basically according to the method described above in example 17, was preparing compounds that meet this invention listed below in examples 18 to 24 (see table. 4).

Example 18

[4S-(alpha, alpha 1a)] -4,7-bis(dimethylamino)- 1,4,4 a,5,5 a,6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-9- [[[(2-hydroxyethyl)methylamino]acetyl] amino]-1,11-dioxo-2 - naphthacenecarboxamide

Example 19

[4S-(alpha, 12a alpha)]-4,7-bis(dimethylamino)- 1,4,4 a,5,5 a,6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-9- [[[(4-(hydroxybutyl)amino] acetyl] amino]-1,11-dioxo-2 - naphthacenecarboxamide

Example 20

[4S-(alpha, 12a alpha)]-4,7-bis(dimethylamino)- 1,4,4 a,5,5 a,6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11 - dioxo-9-[[(2,2,2-triptorelin)amino]acetyl]-2-naphthacenecarboxamide

Example 21

[4S-(4 alpha, 12a alpha)]-4,7-bis(dimethylamino)-9-[[[(2- foradil)amino] acetyl] amino] -1,4,4 a, 5,5 a,6,11,12 a-octahydro - 3,10,12,12 a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

Example 22

[4S-(alpha, 12a alpha)]-4,7-bis(dimethylamino)- 1,4,4 a,5,5 a,6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11 - dioxo-9-[[[[(2-(1-piperidinyl)ethyl]amino]acetyl]amino]-2 - naphthacenecarboxamide

Example 23

[4S-(alpha, 12a alpha)]-4,7-bittangabee

Example 24

[4S-(4 alpha, 12a alpha)]-4,7-bis(dimethylamino)- 1,4,4 a,5,5 a,6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11 - dioxo-9-[[(1-piperidylamine)acetyl]amino]-2 - naphthacenecarboxamide

Example 25

[4S-(alpha, 12a alpha)] -4,7-bis(dimethylamino)- 1,4,4 a,5,5 a,6,11,12 a-octahydro-3,10,12,12 a-tetrahydroxy-1,11 - dioxo-9-[[[(phenylmethoxy)amino] acetyl]amino]-2 - naphthacenecarboxamide

To 0.50 g of o-benzylhydroxylamine and 2.5 ml of 1,3-dimethyl-2-imidazolidinone added to 0.80 g of sodium bicarbonate. The mixture was stirred at room temperature for 2 h, filtered, and the filtrate was added to 0.10 g of product from example 7A. The reaction solution was stirred at room temperature for 2 h and then added to 100 ml of a simple diethyl ether. The resulting precipitate was collected and dried, resulting in received from 0.90 g of the desired product. Method of mass spectrometry (fast atom bombardment) found that the ratio of mass-to-charge m/z is 636 (M + H) (molecular formation, the retaining hydrogen).

Examples preparative forms of pharmaceutical compositions.

1. Injection

Ingredients - Number

The compound of example 6 110 mg

Water for injection 5 ml

Dried Wymore tinavie capsules

Ingredients - Number

The compound of example 17, 50 mg

Microcrystalline cellulose - 70

Gelatin - 25

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1. 7-(substituted)-9-(substituted-glycyl)amido-6-demethyl-6-desoximetasone General formula

< / BR>
where R represents a failure halogen selected from bromine, chlorine, fluorine or iodine, or a group NR1R2and, when R represents a group NR1R2and R1represents hydrogen, R2represents methyl, ethyl, n-through the group, and when R1represents a methyl or ethyl group, R2represents methyl, ethyl, n-sawn, n-boutelou group;

R3selected from the group comprising hydrogen, (C4- C8)alkyl group with straight or branched chain selected from butyl, isobutyl, penttila, carboxyl (C1- C8)alkyl group;

R4selected from hydrogen, methyl or ethyl; when R3not identical to R4the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the Deputy W) may respond to either the racemate (DL) or the individual enantiomers (L or D);

W is selected from hydroxylamine selected from heptyl, Attila, undecyl and the diastereomers and enantiomers mentioned branched alkyl monosubstituted amino group; (C1- C4) foraminotomy straight or branched chain selected from trifloromethyl, 2,2,2-triptoreline; amino, monosubstituted by cyclopropyl, propanolol; 2-phenylaminopropyl, substituted (C6- C10) aryl monosubstituted amino group (the substituents selected from (C1- C4)-alkoxy, (C1- C4)alkoxycarbonyl; and (C2- C8)-azacycloheptane and substituted (C2- C8)azacycloheptane group, the substituents selected from 4-methylpiperidine, 4-hydroxypiperidine; 2-(C1- C3)alkylpiperazine; thiomorpholine; 2-pyridylmethylamine; benzyloxyresorufin;

or R3and W taken together are -(CH2)n(R5)N-, where n is equal to three, where R5is TRIFLUOROACETYL,

or their pharmacologically acceptable organic or inorganic salts or metal complexes.

2. Connection on p. 1, in which R is a halogen selected from bromine, chlorine and iodine, or a group-NR1R2; and, when R represents a group-NR1R2and R1is Cobos hydrogen; R4selected from hydrogen, methyl or ethyl when R3not identical to R4the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the Deputy W) can respond or the racemate (DL) or the individual enantiomers (L or D); W is selected from (C7- C12) alkyl (straight or branched chain)monosubstituted amino group with substituents selected from heptyl, Attila, undecyl and the diastereomers and enantiomers mentioned branched alkyl monosubstituted amino group; (C2) foraminotomy selected from 2,2,2-triptoreline; amino, monosubstituted by cyclopropyl, propanolol; and (C2- C7)azacycloheptane and substituted (C2- C7)azacycloheptane group, the substituents selected from 4-methylpiperidine, 4-hydroxypiperidine of thiomorpholine, 2-pyridylmethylamine, or its pharmacologically acceptable organic or inorganic salts or metal complexes.

3. The compound of formula III

< / BR>
where Y is selected from (CH2)nX, n = 0, 1, X represents a halogen selected from bromine, chlorine, fluorine or iodine;

R is a group-NR1R2where R1represents hydrogen, methyl, ethyl,

R2Pres the8)-alkyl group selected from butyl, isobutyl, penttila, carboxyl (C1- C8)alkyl group;

R4selected from hydrogen, methyl, ethyl, propyl; when R3not identical, R4the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the Deputy Y) may respond to either the racemate (DL) or the individual enantiomers (L or D)

or its pharmacologically acceptable organic or inorganic salts or metal complexes.

4. Connection on p. 3, in which Y is selected from (CH2)nX, where n is 0, 1, X represents a halogen selected from bromine, chlorine, fluorine or iodine; R represents a group-NR1R2; R1is methyl or ethyl; R2represents methyl or ethyl; R3selected from hydrogen; R4selected from hydrogen, methyl or ethyl; when R3not identical, R4the stereochemistry of the asymmetric carbon atom (i.e. the carbon bearing the Deputy W) may respond to either the racemate (DL) or the individual enantiomers (L or D), or its pharmacologically acceptable organic and inorganic salts or metal complexes.

5. Connection under item 1 or 2, characterized in that the salts or complexes include chlorostyrene, cysteine, fumaric, glycolate, maleate, succinate, tartrate, alkylsulfonate, arylsulfonate, salts of aluminum, calcium, iron, magnesium or manganese.

6. Connection on p. 1, representing

[4S-(alpha, 12A alpha)]-9-[[[(cyclopropylmethyl amino]-acetyl]amino]-4,7-bis(dimethylamino)-1,4,4 and, 5,5 and, 6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide the dihydrochloride;

[4S-(alpha, 12A alpha)]-9-[[[(2,2-diatexite)amino]-acetyl]amino]-4,7-bis(dimethylamino)-1,4,4 and, 5,5 and, 6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide the dihydrochloride;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-1,4,4 and,5,5 a,6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-9-[[[2-(methoxyethyl)amino] acetyl] amino-1,11-dioxo-2-naphthacenecarboxamide the dihydrochloride;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-1,4,4 and,5,5 a,6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-1,11-dioxo-9-[[(2-propylamino)acetyl] amino]-2-naphthacenecarboxamide the dihydrochloride;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-1,4,4 and,5,5 a,6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-9-[[[(3-methoxypropyl)amino] acetyl]amino] -1,11-dioxo-2-naphthacenecarboxamide the dihydrochloride;

[7S-(alpha, 10A alpha)] -N-[9-(aminocarbonyl)-4,7-bis(dimethylamino)-5,5 a,6,6,7,10,10 and 12 octahydro-1,8,10 and 11-carbonyl)-4,7-bis(dimethylamino)-5,5 and, 6,6 and, 7,10,10 a, 12 octahydro-1,8,10 and 11,tetrahydroxy-10,12-dioxo-2-naphthalenyl]-4-methyl-1-piperidineacetate the dihydrochloride;

[7S-(alpha, 10A alpha)] -N-[9-(aminocarbonyl)-4,7-bis(dimethylamino)-5,5 a,6,6,7,10,10 and 12 octahydro-1,8,10 and 11,tetrahydroxy-10,12-dioxo-2-naphthalenyl]-4-methyl-1-piperazineethanol the dihydrochloride;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-9-[[(heptylamine)acetyl] amino] -1,4,4 and, and 5,5,6,11,12 and octahydro-3,10,12 and tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide the dihydrochloride;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-1,4,4 and,5,5 a,6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-1,11-dioxo-9-[[(undecillion)acetyl] amino]-2-naphthacenecarboxamide the dihydrochloride;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-1,4,4 and,5,5 a,6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-1,11-dioxo-9-[[[(2-pyridinylmethyl)amino] acetyl]amino]-2-naphthacenecarboxamide the dihydrochloride;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-1,4,4 and,5,5 a,6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-9-[[[(2-hydroxyethyl)amino] acetyl] amino] -1,11-dioxo-2-naphthacenecarboxamide monohydrochloride;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-1,4,4 and,5,5 a,6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-9-[[[(2-hydroxyethyl)methylamino] acetyl] amino]-1,11-dioxo-2-naphthacenecarboxamide;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-1,4,4 and 5 is ID;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-1,4,4 and,5,5 a,6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-1,11-dioxo-9-[[(2,2,2-triptorelin)amino] -2-naphthacenecarboxamide;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-9-[[[(2-foradil)amino] acetyl] amino] -1,4,4 and, 5,5 and, 6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-1,4,4 and,5,5 a,6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-1,11-dioxo-9-[[[(2-(1-piperidinyl)ethyl] acetyl]amino-2-naphthacenecarboxamide;

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)1,4,4 and,5,5 a,6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-9-[[[methyl-2-propylamino] acetyl] amino]-1,11-dioxo-2-naphthacenecarboxamide;

[4S-(alpha, 12A alpha)]-4,7 bis(dimethylamino)-1,4,4 and,5,5 a,6,12 and octahydro-3,10,12,14 and tetrahydroxy-hydroxy-1,11-dioxo-9-[[(1-piperidylamine)acetyl]amino]-2-naphthacenecarboxamide; or

[4S-(alpha, 12A alpha)]-4,7-bis(dimethylamino)-1,4,4,4 and,5,5 a,6,11,12 and octahydro-3,10,12,12 and tetrahydroxy-1,11-dioxo-9-[[[(phenylmethoxy)amino] acetyl]amino]-2-naphthacenecarboxamide.

7. The method of obtaining derivatives of desoximetasone, or organic or inorganic salts or complex metal formula:

< / BR>
where R, R3and R4such, as defined in paragraph 1,

characterized in that 9-[(Gai complex metal formula

< / BR>
where R, R3and R4such, as defined in paragraph 3,

subjected to interaction with nucleophilic compound of formula WH, where W has the meanings given in paragraph 1, in a polar aprotic solvent and in the atmosphere of inert gas.

8. A method of obtaining a connection on p. 3, or organic or inorganic salts or complex metal formula

< / BR>
where R, R3and R4such, as defined in paragraph 3,

characterized in that 9-amino-7-(substituted)-6-dimethyl-6-detoxification, or organic or inorganic salt, or a complex metal formula

< / BR>
subject is subjected to interaction with kaleidotile the halide with a straight or branched chain formula

< / BR>
where Y, R3and R4have the meanings given in paragraph 1;

Q is a halogen selected from bromine, chlorine, iodine and fluorine,

in an inert solvent, polar aprotic solvent and in the presence of a base.

9. Method for the prevention, treatment or control of bacterial infections in warm-blooded animals, characterized in that the said animal is administered a pharmacologically effective amount of the compounds under item 1.

10. Pharmaceutical or ecologicheski effective amount of the compounds on p. 1 and a pharmaceutically acceptable carrier.

11. The method according to p. 9, characterized in that bacterial infections are warm-blooded animals caused by bacteria with Tet M - Tet K-resistant determinants.

 

Same patents:

The invention relates to new 1,11-dioxo-2-naphthacenecarboxamide formula I, where X is halogen or triptorelin-sulfonyloxy; R is hydrogen, halogen; NR1R2; R1is hydrogen; R2is methyl; R3is hydrogen, C1-C8- alkyl, C6-C10- aryl, possibly substituted by hydroxy or halogen, R4- H, C1-C6- alkyl, W - amino group, monosubstituted WITH1-C12- alkyl, Deputy specified in paragraph
The invention relates to a new method of producing sulfate [4S-(alpha, 12A alpha)] -9-amino-4-(dimethylamino)-1,4,4 and, 5,5 and, 6,11,12 and octahydro-3,10,12,12-tetrahydro-1,11-dioxo-2-naphthacenecarboxamide named next 9-amino-6-demethyl-6-doxytetracycline, which is an important industrial compound for the synthesis of tetracyclines

The invention relates to a new method of obtaining compounds of formula I listed in the description

The invention relates to organic synthesis and concerns a method for obtaining metatsiklina

The invention relates to biotechnology and relates to a method of processing uterine fluids in the production of oxytetracycline

The invention relates to cyclic urethane compounds and their pharmaceutical compositions suitable for the treatment of humans and other mammals with cardiac arrhythmia and cardiac fibrillation

The invention relates to the field of medicine and relates to a pharmaceutical composition having anticonvulsive and analgesic activity

The invention relates to new chemical substances possessing valuable properties, in particular derivatives pyridyl General formula (I)

< / BR>
where

n is the number 2, 3, 4 or 5,

A - uglerodsesola communication or unbranched Allenova group with 1 to 4 carbon atoms, unsubstituted or substituted by one or two alkyl groups,

X - nitromethylene group, cyanomethylene group, unsubstituted or substituted by a residue R6with the following for R4values except tetrazole, or a group of formula =N-R7where R7is cyano, alkanesulfonyl group, phenylsulfonyl group, phenylalkylamine group, aminosulfonyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, phenylcarbonylamino group, aminocarbonyl group, alkylaminocarbonyl group or dialkylaminoalkyl group,

Y - alkoxygroup, fenoxaprop, allylthiourea, phenylthiourea or a group of the formula-R8NR9where R8means a hydrogen atom, an unbranched or branched alkyl group with 1 to 10 carbon atoms, which is in the 2nd, 3rd or 4th position can be C is POI or peredelnoj group, alkyl group with 1 to 4 carbon atoms, which may optionally be substituted with hydroxyl group in the 2 nd, 3rd or 4th position, cycloalkyl group with 3 or 4 carbon atoms, cycloalkyl group with 5-8 carbon atoms, in which one ethylene bridge can be replaced on-phenylenebis group, bicycloalkyl group with 6 to 8 carbon atoms, unsubstituted or substituted 1, 2 or 3 alkyl groups, adamantly group, alkoxygroup or trimethylsilylethynyl group, and R9is a hydrogen atom or an unbranched alkyl group, or R8and R9together with in between the nitrogen atoms form an unsubstituted or substituted by one or two alkyl groups or phenyl group, cyclic alkalinising with 4 to 6 carbon atoms, in which one ethylene bridge in the provisions of 3.4 can be replaced on-phenylenebis group, morpholinopropan or piperazinone, unsubstituted or substituted in the 4-position of the alkyl group with 1 to 3 carbon atoms or phenyl group,

R1is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms,

R2and R3is a hydrogen atom or together form a carbon-carbon bond,

Pyr - Peregrina group, unsubstituted or sameena the group, alkylaminocarbonyl group, dialkylaminoalkyl group, group, translated in vivo metabolic by carboxyl group or carboxyl group, if Y represents the group R8NR9where R8and R9have the above meaning,

R5is a hydrogen atom or the halogen, alkyl, alkoxy or trifluoromethyl,

all of the aforementioned alkyl and CNS remains, if nothing else is mentioned, have 1 to 3 carbon atoms, and, if nothing else is mentioned, all the above-mentioned phenyl nuclei may be mono - or tizamidine identical or different substituents from the group comprising an atom of fluorine, chlorine, or bromine, alkyl, hydroxyl, alkoxyl, carboxyl, phenyl, nitro-, amino-, alkylamino, dialkylamino, alkanolamine, cyano, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl and dialkylaminoalkyl,< / BR>
their enantiomers, CIS - or TRANS-isomers, if R2and R3together denote a carbon-carbon bond, and their salts

The invention relates to the derivatives of diphenyl, in particular, it relates to derivatives of diphenyl who are antagonistic towards 2-defeminization and/or 2-serotoninreuptake and which is clinically used as a therapeutic-help tools for mental disorders, such as vascular dysfunction brain, aggressive behavior due to senile dementia, mental arousal, pornomania, delirium, hallucination, hyperkinesia, schizophrenia, emotional disorder, depression, neurosis, psycho-physiological disorder and neurosis of fear
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